Increased prevalence of Diabetes and obesity has been termed as the epidemic of 21st century and estimated to exceed 300 million people currently.
Diabetes is associated with a number of complications and also affect a large population. This disease is usually associated with other diseases such as obesity, hyperlipidemia, hypertension and angina. Two most common types of diabetes known are Type I (also referred to as insulin-dependent diabetes mellitus or IDDM) and Type II (also referred to as non-insulin-dependent diabetes mellitus or NIDDM).
The etiology of the different types of diabetes is not the same; however, everyone with diabetes has two things in common: overproduction of glucose by the liver and little or no ability to move glucose out of the blood into the cells where it becomes the body's primary fuel.
Obesity is another major health problem being associated with increased morbidity and mortality. It is a metabolic disorder, in which excess of fat is accumulated in the body. Although, its etiology is unclear, the general feature includes excess of calorie intake than it is consumed.
Pharmacological approaches to the treatment of obesity have been mainly concerned with reducing fat mass by altering the balance between energy intake and expenditure. Many studies have clearly established the link between adiposity and the brain circuitry involved in the regulation of energy homeostasis. Direct and indirect evidence suggest that serotonergic, dopaminergic, adrenergic, cholinergic, endocannabinoid, opioid, and histaminergic pathways in addition to many neuropeptide pathways (e.g. neuropeptide Y and melanocortins) are implicated in the central control of energy intake and expenditure. Hypothalamic centers are also able to sense peripheral hormones involved in the maintenance of body weight and degree of adiposity, such as insulin and leptin, and fat tissue derived peptides.
Drugs aimed at the pathophysiology associated with insulin dependent Type I diabetes and non-insulin dependent Type II diabetes have many potential side effects and do not adequately address the dyslipidemia and hyperglycemia in a high proportion of patients. Treatment is often focused at individual patient needs using diet, exercise, hypoglycemic agents and insulin, but there is a continuing need for novel antidiabetic agents, particularly ones that may be better tolerated with fewer adverse effects.
Similarly, metabolic syndrome (syndrome X) which is characterized by hypertension and its associated pathologies including atherosclerosis, lipidemia, hyperlipidemia and hypercholesterolemia have been associated with decreased insulin sensitivity which can lead to abnormal blood sugar levels when challenged. Myocardial ischemia and micro vascular disease is an established morbidity associated with untreated or poorly controlled metabolic syndrome.
There is a continuing need for novel antiobesity and antidiabetic agents, particularly ones that are well tolerated with few adverse effects.
The present invention is directed to G-protein coupled receptor (GPCR) agonists. In particular, the present invention is directed to agonists of GPR 119 that are useful for the treatment of obesity, e.g. as regulators of satiety, and for the treatment of diabetes.
The present invention is directed to G-protein coupled receptor agonists of GPR 119 that are useful for the treatment of obesity, e.g. as regulators of satiety, and for the treatment of diabetes. GPR 116 is a GPCR identified as SNORF25 in WO00/50562 which discloses both the human and rat receptors. U.S. Pat. No. 6,468,756 also discloses the mouse receptor (accession numbers: AAN95194 (human), AAN95195 (rat) and ANN95196 (mouse)).
In humans, GPR 119 is expressed in the pancreas, small intestine, colon and adipose tissue. A Role of G Protein-Coupled Receptor 119 Expressed in β Cell—in Glycemic Control by enhancing Glucose Dependent Insulin Release was demonstrated by using an agonist of GPR-119 (Endocrinology 148(6):2601-2609). Further the anti obesity effects of GPR-119 agonist which suppress food intake in rats and reduce body weight gain and white adipose tissue deposition upon subchronic oral administration to high-fat-fed rats was also demonstrated (Cell Metabolism 3, 167-175). GPR119 therefore represents a novel and attractive potential target for the therapy of obesity and related metabolic disorders.
International patent applications WO2005061489, WO2007116230, WO2007116229, WO2007003964, WO2007003962, WO2007003961, WO2006070208 discloses heterocyclic derivatives as GPR 119 receptor agonists. However, the therapeutic potential of these compounds to treat diseases has not yet been proved and so there remains the need to develop newer medicines which are better or of comparable efficacy with the present treatment regimes, have lesser side effects and require a lower dosage regime
We herein disclose novel compounds of formula (I) useful as antidiabetic, anti-obesity, hypolipidemic, hypolipoproteinemic, and antihyperglycemic agents which may have additional body weight lowering effect and beneficial effect in the treatment and/or prophylaxis of diseases caused by hyperlipidemia, diseases classified under Syndrome X and atherosclerosis, and methods for their preparation.